Thiazetidinyl-terminated alkylamino ethynyl alanine amino diol compounds for treatment of hypertension

ABSTRACT

Compounds characterized generally as thiazetidinyl-terminated alkylamino ethynyl alanine amino diol derivatives are useful as renin inhibitors for the treatment of hypertension. Compounds of particular interest are those of Formula I ##STR1## wherein A is selected from CO and SO 2  ; wherein X is selected from oxygen atom and methylene; wherein B is a thiazetidinyl group; wherein R 1  is selected from hydrido, methyl, ethyl, isopropyl and n-propyl; wherein R 2  is phenylmethyl; wherein each of R 3  and R 5  is hydrido; wherein R 4  is selected from 
     
         --(CH.sub.2).sub.q --C.tbd.C-V 
    
     wherein V is selected from hydrido and methyl; wherein R 6  is cyclohexylmethyl; wherein R 7  is selected from isobutyl, cyclopropyl and cyclopropylmethyl; wherein q is a number selected from zero through three, inclusive; and wherein n is a number selected from zero through three, inclusive; or a pharmaceutically-acceptable salt thereof.

RELATED APPLICATION

This is a divisional of U.S. application Ser. No. 07/930,069, filed Aug.14, 1992.

FIELD OF THE INVENTION

Renin-inhibiting compounds are known for control of hypertension. Ofparticular interest herein are compounds useful as renin inhibitingagents.

BACKGROUND OF THE INVENTION

Renin is a proteolytic enzyme produced and secreted into the bloodstreamby the juxtaglomerular cells of the kidney. In the bloodstream, renincleaves a peptide bond in the serum protein angiotensinogen to produce adecapeptide known as angiotensin I. A second enzyme known as angiotensinconverting enzyme, cleaves angiotensin I to produce the octapeptideknown as angiotensin II. Angiotensin II is a potent pressor agentresponsible for vasoconstriction and elevation of cardiovascularpressure. Attempts have been made to control hypertension by blockingthe action of renin or by blocking the formation of angiotensin II inthe body with inhibitors of angiotensin I converting enzyme.

Classes of compounds published as inhibitors of the action of renin onangiotensinogen include renin antibodies, pepstatin and its analogs,phospholipids, angiotensinogen analogs, pro-renin related analogs andpeptide aldehydes.

A peptide isolated from actinomyces has been reported as an inhibitor ofaspartyl proteases such as pepsin, cathepsin D and renin [Umezawa et al,in J. Antibiot. (Tokyo), 23, 259-262 (1970)]. This peptide, known aspepstatin, was found to reduce blood pressure in vivo after theinjection of hog renin into nephrectomized rats [Gross et al, Science,175, 656 (1971)]. Pepstatin has the disadvantages of low solubility andof inhibiting acid proteases in addition to renin. Modified pepstatinshave been synthesized in an attempt to increase the specificity forhuman renin over other physiologically important enzymes. While somedegree of specificity has been achieved, this approach has led to ratherhigh molecular weight hepta- and octapeptides [Boger et al, Nature, 303,81 (1983)]. High molecular weight peptides are generally consideredundesirable as drugs because gastrointestinal absorption is impaired andplasma stability is compromised.

Short peptide aldehydes have been reported as renin inhibitors [Kokubuet al, Biochim. Biophys. Res. Commun., 118, 929 (1984); Castro et al,FEBS Lett., 167, 273 (1984)]. Such compounds have a reactive C-terminalaldehyde group and would likely be unstable in vivo.

Other peptidyl compounds have been described as renin inhibitors. EPAppl. #128,762, published 18 Dec. 1984, describes dipeptide andtripeptide glyco-containing compounds as renin inhibitors [also seeHanson et al, Biochm. Biophys. Res. Comm., 132, 155-161 (1985), 146,959-963 (1987)]. EP Appl. #181,110, published 14 May 1986, describesdipeptide histidine derivatives as renin inhibitors. EP Appl. #186,977published 9 Jul. 1986 describes renin-inhibiting compounds containing analkynyl moiety, specifically a propargyl glycine moiety, attached to themain chain between the N-terminus and the C-terminus, such asN-[4(S)-[(N)-[bis(1-naphthylmethyl)acetyl]-DL-propargylglyclamino]-3(S)-hydroxy-6-methylheptanoyl]-L-isoleucinol.EP Appl. #189,203, published 30 Jul. 1986, describes peptidylaminodiolsas renin inhibitors. EP Appl. #200,406, published 10 Dec. 1986,describes alkylnaphthylmethylpropionyl-histidyl aminohydroxy alkanoatesas renin inhibitors. EP Appl. #216,539, published 1 Apr. 1987, describesalkylnaphthylmethylpropionyl aminoacyl aminoalkanoate compounds as renininhibitors orally administered for treatment of renin-associatedhypertension. EP Appl. #229,667, published 22 Jul. 1987, describes acylα-aminoacyl aminodiol compounds having a piperazinylcarbonyl or analkylaminoalkylcarbonyl terminal group at the N-amino acid terminus,such as 2(S)-{[(1-piperazinyl)carbonyl]-oxy]-3-phenylpropionyl}-Phe-Hisamide of 2(S)-amino-1-cyclohexyl-3(R), 4(S)-dihydroxy-6-methylheptane.PCT Application No. WO 87/04349, published 30 Jul. 1987, describesaminocarbonyl aminoacyl hydroxyether derivatives having analkylamino-containing terminal substituent and which are described ashaving renin-inhibiting activity for use in treating hypertension. EPAppl. #300,189 published 25 Jan. 1989 describes amino acid monohydricderivatives having an alkylamino-alkylamino N-terminus and aβ-alanine-histidine or sarcosyl-histidine attached to the main chainbetween the N-terminus and the C-terminus, which derivatives arementioned as useful in treating hypertension. U.S. Pat. No. 4,902,706which issued 13 Feb. 1990 describes a series ofhistidineamide-containing amino alkylaminocarbonyl-H-terminal aminodiolderivatives for use as renin inhibitors. U.S. Pat. No. 5,032,577 whichissued 16 Jul. 1991 describes a series ofhistidineamide-aminodiol-containing renin inhibitors.

Heterocyclic-terminated aminodiol compounds have been described as renininhibitors. For example, EP #410,260 published 30 Jan. 1991 describes aseries of heterocyclic-terminated peptidyl aminodiol renin inhibitorcompounds having utility as antihypertensive agents, wherein specificcompounds are described having various terminal heterocyclic groups suchas morpholino, pyridinyl, piperazinyl, imidazolyl, pyrazolyl and indolylgroups, including the compound(2R)-2-benzyl-3-[(2-morpholin-4-ylethyl)methylaminocarbonyl]propionyl-L-4-thiazolyl)Alaamide of (2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane.EP #456,185 published 13 Nov. 1991 describes a series ofheterocyclic-terminated sulfonamide-containing peptidyl aminodiol renininhibitor compounds having utility as antihypertensive agents, whereinspecific compounds are described having various terminal heterocyclicgroups such as piperazinyl, oxo-substituted piperazinyl and morpholinogroups.

DESCRIPTION OF THE INVENTION

Morpholino/thiomorpholino-terminated alkylamino ethynyl alanine aminodiol compounds, having utility as renin inhibitors for treatment ofhypertension in a subject, constitute a family of compounds of generalFormula I: ##STR2## wherein A is selected from CO and SO₂ ; wherein X isselected from oxygen atom and methylene; wherein R₁ is selected fromhydrido and alkyl; wherein B is a saturated heterocyclic ring system offour to ten ring members containing one nitrogen atom and one otherheteroatom selected from oxygen atom and sulfur atom as ring members,wherein said ring system may be monocyclic or bicyclic and may be fusedto a benzene or cyclohexane ring, wherein the point of attachment of Bto the backbone of the structure of Formula I may be through a bond toany substitutable position on said heterocyclic ring system of B andwherein any substitutable position of B may be optionally substitutedwith one or more radicals selected from alkyl, alkoxy, alkenyl, alkynyl,halo, trifluoromethyl, oxo, cyano and phenyl, and wherein the saidheterocyclic ring nitrogen atom may be combined with oxygen to form anN-oxide; wherein R₂ is selected from alkyl, cycloalkylalkyl,acylaminoalkyl, phenylalkyl and naphthylalkyl, and wherein the cyclicportion of any of said phenylalkyl, cycloalkylalkyl and naphthylalkylgroups may be substituted by one or more radicals selected from halo,hydroxy, alkoxy and alkyl; wherein each of R₃ and R₅ is independentlyselected from hydrido and alkyl; wherein R₄ is selected from ##STR3##wherein V is selected from hydrido, alkyl, benzyl and phenyl; whereineach of R₈ and R₉ is a radical independently selected from hydrido,alkyl, alkenyl and phenyl; wherein R₆ is selected from alkyl,cycloalkylalkyl and phenylalkyl, any one of which may be substitutedwith one or more groups selected from alkyl, hydroxy and alkoxy; whereinR₇ is selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl,hydroxyalkyl and alkenyl; wherein p is a number selected from zerothrough five, inclusive; wherein q is a number selected from zerothrough five, inclusive; and wherein n is a number selected from zerothrough five, inclusive; or a pharmaceutically-acceptable salt thereof.

A preferred family of compounds consists of compounds of Formula Iwherein A is selected from CO and SO₂ ; wherein X is selected fromoxygen atom and methylene; wherein R₁ is selected from hydrido andalkyl; wherein B is a saturated heterocyclic ring system of four to tenring members containing one nitrogen atom and one other heteroatomselected from oxygen atom and sulfur atom as ring members, wherein saidring system may be monocyclic or bicyclic and may be fused to a benzeneor cyclohexane ring, wherein the point of attachment of B to thebackbone of the structure of Formula I may be through a bond to anysubstitutable position on said heterocyclic ring system of B and whereinany substitutable position of B may be optionally substituted with oneor more radicals selected from alkyl, alkoxy, alkenyl, alkynyl, halo,trifluoromethyl, oxo, cyano and phenyl, and wherein the saidheterocyclic ring nitrogen atom may be combined with oxygen to form anN-oxide; wherein R₂ is selected from cyclohexylmethyl, phenylmethyl andnaphthylmethyl, and wherein the cyclic portion of any of saidphenylmethyl, cyclohexylmethyl and naphthylmethyl groups may besubstituted by one or more radicals selected from halo, hydroxy, alkoxyand alkyl; wherein each of R₃ and R₅ is independently selected fromhydrido and methyl; wherein R₄ is selected from

    --(CH.sub.2).sub.q --C.tbd.C--V

wherein V is selected from hydrido and alkyl; wherein R₆ is selectedfrom cyclohexylmethyl and phenylmethyl, either one of which may besubstituted with one or more groups selected from alkyl, hydroxy andalkoxy; wherein R₇ is selected from alkyl, cycloalkyl andcycloalkylalkyl; wherein q is a number selected from zero through three,inclusive; and wherein n is a number selected from zero through five,inclusive; or a pharmaceutically-acceptable salt thereof.

A more preferred family of compounds consists of compounds of Formula Iwherein A is selected from CO and SO₂ ; wherein X is selected fromoxygen atom and methylene; wherein R₁ is selected from hydrido, methyl,ethyl, isopropyl and n-propyl; wherein B is a heterocyclic ring systemselected from morpholinyl, thiazetidinyl, oxazetidinyl,2-oxomorpholinyl, thiomorpholinyl, thiazolidinyl, oxazepinyl,oxazocinyl, thiazepinyl, thiazocinyl and3-oxa-8-azabicyclo[3.2.1]octanyl and wherein any of said heterocyclicring systems may be fused to a benzene or cyclohexane ring, wherein thepoint of attachment of B may be through a bond to any substitutableposition on said heterocyclic ring system and where any substitutableposition of B may be optionally substituted with one or more radicalsselected from alkyl, alkoxy, alkenyl, alkynyl, halo, trifluoromethyl,oxo, cyano and phenyl, and wherein the nitrogen atom ring member of Bmay be combined with oxygen to form an N-oxide; wherein R₂ is selectedfrom cyclohexylmethyl, phenylmethyl and naphthylmethyl, and wherein thecyclic portion of any of said phenylmethyl, cyclohexylmethyl andnaphthylmethyl groups may be substituted by one or more radicalsselected from halo, hydroxy, alkoxy and alkyl; wherein each of R₃ and R₅is independently selected from hydrido and methyl; wherein R₄ isselected from

    --(CH.sub.2).sub.q --C.tbd.C--V

wherein V is selected from hydrido and alkyl; wherein R₆ is selectedfrom cyclohexylmethyl and phenylmethyl, either one of which may besubstituted with one or more groups selected from alkyl, hydroxy andalkoxy; wherein R₇ is selected from alkyl, cycloalkyl andcycloalkylalkyl; wherein q is a number selected from zero through three,inclusive; and wherein n is a number selected from zero through five,inclusive; or a pharmaceutically-acceptable salt thereof.

An even more preferred family of compounds consists of compounds FormulaI wherein A is selected from CO and SO₂ ; wherein X is selected fromoxygen atom and methylene; wherein R₁ is selected from hydrido, methyl,ethyl, isopropyl and n-propyl; wherein B is a heterocyclic ring systemselected from the group consisting of: ##STR4## wherein said B group isattached to the backbone of the structure of Formula I through the bondon each B group bisected by the wavy line, and wherein any substitutableposition may be optionally substituted with one or more radicalsselected from alkyl, alkoxy, alkenyl, alkynyl, halo, trifluoromethyl,oxo, cyano and phenyl, and wherein the nitrogen atom ring member of Bmay be combined with oxygen to form an N-oxide; wherein R₂ is selectedfrom phenylmethyl and wherein the cyclic portion of said phenylmethylgroup may be substituted by one or more radicals selected from halo,hydroxy, alkoxy and alkyl; wherein each of R₃ and R₅ is independentlyselected from hydrido and methyl; wherein R₄ is selected from

    --(CH.sub.2).sub.q --C.tbd.C--V

wherein V is selected from hydrido and methyl; wherein R₆ iscyclohexylmethyl; wherein R₇ is selected from isobutyl, cyclopropyl andcyclopropylmethyl; wherein q is a number selected from zero throughthree, inclusive; and wherein n is a number selected from zero throughthree, inclusive; or a pharmaceutically-acceptable salt thereof.

A highly preferred family of compounds consists of compounds of FormulaI wherein A is selected from CO and SO₂ ; wherein X is selected fromoxygen atom and methylene; wherein R₁ is selected from hydrido, methyl,ethyl, isopropyl and n-propyl; wherein R₂ is phenylmethyl; wherein eachof R₃ and R₅ is hydrido; wherein R₄ is selected from

    --(CH.sub.2).sub.q --C.tbd.C--V

wherein V is selected from hydrido and methyl; wherein R₆ iscyclohexylmethyl; wherein R₇ is selected from isobutyl, cyclopropyl andcyclopropylmethyl; wherein q is a number selected from zero throughthree, inclusive; and wherein n is a number selected from zero throughthree, inclusive; or a pharmaceutically-acceptable salt thereof.

The term "hydrido" denotes a single hydrogen atom (H). This hydridogroup may be attached, for example, to an oxygen atom to form a hydroxylgroup; or, as another example, one hydrido group may be attached to acarbon atom to form a >CH-- group; or, as another example, two hydridogroups may be attached to a carbon atom to form a --CH₂ -- group. Wherethe term "alkyl" is used, either alone or within other terms such as"haloalkyl" and "hydroxyalkyl", the term "alkyl" embraces linear orbranched radicals having one to about twenty carbon atoms or,preferably, one to about twelve carbon atoms. More preferred alkylradicals are "lower alkyl" radicals having one to about ten carbonatoms. Most preferred are lower alkyl radicals having one to about sixcarbon atoms. The term "cycloalkyl" embraces cyclic radicals havingthree to about ten ring carbon atoms, preferably three to about sixcarbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl andcyclohexyl. The term "alkenyl" embraces linear or branched radicalshaving two to about twenty carbon atoms, preferably three to about tencarbon atoms, and containing at least one carbon-carbon double bond,which carbon-carbon double bond may have either cis or trans geometrywithin the alkenyl moiety. The term "alkynyl" embraces linear orbranched radicals having two to about twenty carbon atoms, preferablytwo to about ten carbon atoms, and containing at least one carbon-carbontriple bond. The term "alkoxy" embraces linear or branchedoxy-containing radicals having alkyl portions of one to about ten carbonatoms, such as methoxy group. The "alkoxy" radical may be furthersubstituted with one or more halo atoms, such as fluoro, chloro orbromo, to provide haloalkoxy groups. The term "sulfonyl", whether usedalone or linked to other terms, denotes the divalent radical SO₂. Theterm "acyl" whether used alone, or within a term such as acyloxy,denotes a radical provided by the residue after removal of hydroxyl froman organic acid, examples of such radical being acetyl and benzoyl."Lower alkanoyl" is an example of a more preferred sub-class of acyl.The term "alkenylalkyl" denotes a radical having a double-bondunsaturation site between two carbons, and which radical may consist ofonly two carbons or may be further substituted with alkyl groups whichmay optionally contain additional double-bond unsaturation. A groupembraced by the term "heterocyclic ring system" may be attached to thebackbone of Formula I as a substituent through a carbon atom of thehetero ring system, or may be attached through a carbon atom of a moietysubstituted on a hetero ring-member carbon atom. Also, suchhetero-containing group may be attached through a ring nitrogen atom.For any of the foregoing defined radicals, preferred radicals are thosecontaining from one to about fifteen carbon atoms.

Specific examples of alkyl groups are methyl, ethyl, n-propyl,isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl,isopentyl, methylbutyl, dimethylbutyl and neopentyl. Typical alkenyl andalkynyl groups may have one unsaturated bond, such as an allyl group, ormay have a plurality of unsaturated bonds, with such plurality of bondseither adjacent, such as allene-type structures, or in conjugation, orseparated by several saturated carbons.

Also included in the family of compounds of Formula I are isomericforms, including diastereoisomers, and the pharmaceutically-acceptablesalts thereof. The term "pharmaceutically-acceptable salts" embracessalts commonly used to form alkali metal salts and to form additionsalts of free acids or free bases. The nature of the salt is notcritical, provided that it is pharmaceutically-acceptable. Suitablepharmaceutically-acceptable acid addition salts of compounds of FormulaI may be prepared from an inorganic acid or from an organic acid.Examples of such inorganic acids are hydrochloric, hydrobromic,hydroiodic, nitric, carbonic, sulfuric and phosphoric acid. Appropriateorganic acids may be selected from aliphatic, cycloaliphatic, aromatic,araliphatic, heterocyclic, carboxylic and sulfonic classes of organicacids, example of which are formic, acetic, propionic, succinic,glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic,glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic,anthranilic, p-hydroxybenzoic, salicyclic, phenylacetic, mandelic,embonic (pamoic), methansulfonic, ethanesulfonic,2-hydroxyethanesulfonic, pantothenic, benzenesulfonic, toluenesulfonic,sulfanilic, mesylic, cyclohexylaminosulfonic, stearic, algenic,β-hydroxybutyric, malonic, galactaric and galacturonic acid. Suitablepharmaceutically-acceptable base addition salts of compounds of FormulaI include metallic salts made from aluminium, calcium, lithium,magnesium, potassium, sodium and zinc or organic salts made fromN,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine,ethylenediamine, meglumine (N-methylglucamine) and procaine. Alsoincluded within the phrase "pharmaceutically-acceptable salts" are"quaternary" salts or salts of "onium" cations, such as ammonium,morpholinium and piperazinium cations, as well as any substitutedderivatives of these cations where the salt is formed on the nitrogenatom lone pair of electrons. All of these salts may be prepared byconventional means from the corresponding compound of Formula I byreacting, for example, the appropriate acid or base with the compound ofFormula I.

Compounds of Formula I would be useful to treat variouscirculatory-related disorders. As used herein, the term"circulatory-related" disorder is intended to embrace cardiovasculardisorders and disorders of the circulatory system, as well as disordersrelated to the circulatory system such as ophthalmic disorders includingglaucoma. In particular, compounds of Formula I would be useful toinhibit enzymatic conversion of angiotensinogen to angiotensin I. Whenadministered orally, a compound of Formula I would be expected toinhibit plasma renin activity and, consequently, lower blood pressure ina patient such as a mammalian subject (e.g., a human subject). Thus,compounds of Formula I would be therapeutically useful in methods fortreating hypertension by administering to a hypertensive subject atherapeutically-effective amount of a compound of Formula I. The phrase"hypertensive subject" means, in this context, a subject suffering fromor afflicted with the effects of hypertension or susceptible to ahypertensive condition if not treated to prevent or control suchhypertension. Other examples of circulatory-related disorders whichcould be treated by compounds of the invention include congestive heartfailure, renal failure and glaucoma.

Description of the Synthetic Methods for the Preparation of the ReninInhibitors of the Invention ##STR5##

Wherein R₁ -R₇, X, A, B, and n are as defined before.

Synthetic Scheme 1 (Preparation of Compounds of Formula I)

A suitably protected amino aldehyde 1 is treated with a Grignard reagentor other organometallic reagent, preferably vinylmagnesium bromide, toobtain the vinyl carbinol 2. This material, suitably protected, isoxidized, preferably with ozone, followed by dimethyl sulfide or zinctreatment, to give intermediate 3. The preceeding process is exemplifiedin Hanson, et al., J. Org. Chem. 50, 5399 (1985). This aldehyde isreacted with an organometallic reagent such as isobutylmagnesiumchloride to give intermediate 4. Other suitable organometallic reagentsinclude ethylmagnesium bromide, vinylmagnesium bromide,cyclopropylmagnesium bromide, and allylmagnesium bromide, but thechoices are not limited to these reagents. After the formation of 4,further transformation of the added side chain is permitted, beforegoing on the next depicted step. For example, the compound 4 derivedfrom the addition of allylmagnesium bromide may be cyclopropanated viadiazomethane and rhodium acetate, to give a cyclopropylmethyl sidechain. Compound 4 is deprotected then coupled, using standardamide/peptide coupling methodology to protected triple bond-containing(ethynyl) amino acid derivatives 5 to give compound 6. These standardcoupling procedures such as the carbodiimide, active ester(N-hydroxysuccinimide), and mixed carbonic anhydride methods are shownin Benoiton, et al. J. Org. Chem. 48, 2939 (1983) and Bodansky, et al."Peptide Synthesis", Wiley (1976). Ethynyl-containing amino acidderivatives may be prepared by using procedures such as found inSchollkopf, Tetrahedron 39, 2085 (1983). Intermediate 6 is thendeprotected, then coupled to intermediate 7 using the standardamide/peptide coupling methodology, to give compounds of Formula I.Suitable protecting groups may be selected from among those reviewed byR. Geiger in "The Peptides", Academic Press, N.Y. vol. 2 (1979). Forexample, P₁ and P₃ may be Boc or Cbz; P₂ may be a typical oxygenprotective group such as acetyl or t-butyldimethylsilyl. ##STR6##

Wherein R₁, R₂, X, A, B and n are as defined before.

Synthetic Scheme 2 (Preparation of Compounds of Formula I)

Intermediate 7 may be prepared according to the schematic of SyntheticScheme 2. Intermediate 7 is prepared by coupling theheterocyclicalkylamine 8 to mono-protected carboxylic acid 9. Carboxylicacid or sulfonic acid 9 is a mono-activated moiety by virtue of asuitable leaving group Q which may be chloride, bromide, fluoride,N-hydroxysuccinimido, p-toluenesulfonyloxy or isobutyloxycarbonyloxy,but is not limited to these groups. After coupling, protecting group P₄is removed (if P₄ is a benzyl group, hydrogenolysis overpalladium-on-carbon (Pd-C) is performed) to give intermediate amino acid7.

Abbreviations used:

P₁ is an N-protecting group; P₂ is H or an oxygen protecting group; P₃is an N-protecting group; P₄ is an oxygen protecting group such asbenzyl or methyl; Q is a leaving group; Boc is t-butyloxycarbonyl; Cbzis carbobenzoxy.

The following Steps constitute specific exemplification of methods toprepare starting materials and intermediates embraced by the foregoinggeneric synthetic scheme. Those skilled in the art will readilyunderstand that known variations of the conditions and processes of thefollowing preparative procedures can be used to prepare the compounds ofthe Steps. All temperatures expressed are in degrees Centigrade.

Step 1

(2R,3S)-N-[(tert-Butyloxy)carbonyl]-3-amino-2-acetoxy-4-phenylbutanal

Ozone/oxygen was bubbled at -70° C. into a solution of(3S,4S)-N-[(tert-Butyloxy)carbonyl]-4-amino-3-acetoxy-5-phenylpentene(2.55 g, 8.0 mmol) [prepared by the method of Hanson et al., J. Org.Chem., 50, 5399 (1985)] in 100 mL of methylene chloride until a deepblue color persisted. Oxygen was introduced until the blue colorcompletely faded, then 3.0 mL of Me₂ S was added and the solution wasallowed to warm to 0°-5° C. and stand overnight. The solvent was removedat 0° C. under vacuum yielding the title compound as a thick yellow oilwhich was used without further purification.

Step 2

(2S,3R,4S)-N-[(tert-Butyloxy)carbonyl]-2-amino-1-phenyl-3,4-dihydroxy-6-methylheptane

The title compound of Step 1 was dissolved under nitrogen in 100 mL ofdry THF and cooled to -70° C. To this solution was added 13 mL (26 mmol)of a 2.0M solution of isobutylmagnesium chloride in ether and thestirred mixture was allowed to warm to room temperature and stir for 2hrs. After decomposition with MeOH/H₂ O the mixture was diluted withether, washed with saturated NH₄ Cl solution twice and dried withmagnesium sulfate and the solvents evaporated under vacuum. The residuewas allowed to stand overnight in 80% MeOH-H₂ O containing excessammonium hydroxide. The MeOH was stripped off and the mixture wasextracted with ether. These extracts were combined, washed with water,dilute KHSO₄, then dried and evaporated to give 2.36 g of a yellow glasswhich crystallized from 50 mL of pentane on standing overnight. Theyellow-white powder obtained was recrystallized from ether-hexane andfurnished the title compound (0.41 g) as white, hairy needles, mp134°-136° C., Rf (ether): single spot, 0.6. By chromatography of themother liquors and crystallization of the appropriate fractions, anadditional 0.22 g of product, mp 138°-139° C., was obtained.

Anal: Calcd. for C₁₉ H₃₁ NO₄ : C, 67.62; H, 9.26; N, 4.15. Found: C,67.51; H, 9.43; N, 4.24.

Step 3

(2S,3R,4S)-N-[(tert-Butyloxy)carbonyl]-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane

The title compound of Step 2 (0.27 g) was reduced in MeOH with 60 psi H₂at 60° in 3 hrs using 5% Rh/C catalyst. After filtering, the solvent wasstripped off and the white crystals were recrystallized from CH₂ Cl₂-hexane to furnish tiny needles of the title compound 0.19 g, mp126°-128° C.); further recrystallization gave mp 128.5°-129.5° C. Rf(ether): single spot, 0.8. Anal: Calcd. for C₁₉ H₃₇ NO₄ : C, 66.43; H,10.86, N, 4.08. Found: C, 66.43; H, 11.01; N, 4.03.

Step 4

(2S,3R,4S) 2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane

The title compound of Step 3 (10 g) was dissolved 6.9N HCl in dioxane(300 mL). The mixture was stirred for 30 minutes at room temperature.The solvent was removed in vacuo and to the residue was added 5% aqueoussodium hydroxide (30 mL) until a pH of 14 was obtained. This mixture wasextracted with ether and the ether extracted was washed with water andbrine, then the solvent was evaporated to give the title compound (7.3g, 100% yield). 300 MHz ¹ H NMR: consistent with proposed structure.Anal. calcd for C₁₄ H₂₉ NO₂ : C, 69.07; H, 12.01; N, 5.78. Found: C,69.19; H, 12.34; N, 5.78.

Step 5

L-Boc-C-propargylglycine

L-C-Propargylglycine (10 g) [prepared by the method of Schwyzer et al.,Helv. Chim. Acta, 59, 2181 (1976)] was suspended in tetrahydrofuran (30mL). Water (30 mL), potassium carbonate (36.7 g), anddi-tert-butyl-dicarbonate (21.9 g) were added. Additional water wasadded to produce a solution which was stirred for 12 hours at roomtemperature. The organic solvent was then evaporated and the aqueoussolution was washed with ether, then acidified to pH 3 with 1N aqueouscitric acid. The solution was extracted with methylene chloride and thesolvent evaporated to give the title compound (18.9 g, 97% yield), usedwithout further purification.

Step 6

Boc L-C-propargylglycine amide of 2S,3R,4S)2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane

Boc L-C-propargylglycine (1.2 g) was dissolved in methylene chloride (5mL) and N-methyl piperidine (0.57 g) was added. The mixture was cooledto zero degrees centigrade and isobutyl chloroformate (0.78 g) wasadded. The mixture was stirred for 10 minutes whereupon the titlecompound of Step 4 (1.4 g) in methylene chloride (5 mL) was added andthis mixture stirred for 15 minutes at 0° C. and 4° C. for 12 hours. Thereaction mixture was washed successively with 1N citric acid, saturatedsodium hydrogen carbonate, water and brine. The organic layer was driedover magnesium sulfate and evaporated to dryness. The residue waschromatographed on silica gel to give the title compound as a colorlessoil. 300 MHz ¹ H NMR: consistent with proposed structure.

Step 7

L-C-propargylglycine amide of (2S,3R,4S)2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane

The title compound of Step 6 (0.76 g) was dissolved in a mixture oftrifluoroacetic acid (4.9 mL) and methylene chloride (4.9 mL), andstirred for 30 minutes at room temperature. The solvent was thenevaporated and the residue taken up in ethyl acetate. The organic layerwas washed with saturated sodium hydrogen carbonate, water and brine,then dried over magnesium sulfate and evaporated to give the titleamine. 300 MHz ¹ H NMR: consistent with proposed structure.

Step 8

2R-(Phenylmethyl)butanedioic acid, 1-(phenylmethyl) ester,dicyclohexylammonium salt

To a slurry of 4-(4-methoxybenzyl)itaconate [prepared by the method ofTalley in U.S. Pat. No. 4,939,288] (50 g) in toluene (250 mL) was added1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 30.4 g) in one portion. Then asolution of benzyl bromide (34.2 g) in toluene (50 mL) was addeddropwise over 0.5 hour. The reaction was stirred for 0.5 hour at roomtemperature and then poured into a separatory funnel. The mixture waswashed with 3N HCl, aqueous sodium bicarbonate, brine and dried overmagnesium sulfate. The solvent was evaporated to give a clear mobileliquid (68 g). Chromatography on silica gel, eluting with from 100%hexane to 25% ethyl acetate gave pure 1-(benzyl)-4-(4-methoxybenzyl)itaconate (55 g, 81% yield). A large Fisher-Parter bottle was chargedwith this itaconate (41 g), triethylamine (36 g), palladium acetate (380mg), tri-o-tolylphosphine (1.04 g) and iodobenzene (24.7 g). The bottlewas sealed and flushed with nitrogen and placed in an oil bath andheated for 70 minutes. The residue was chromatographed on silica gel,eluting with 100% hexanes until the less polar impurities were removed.Eluting with 10% ethyl acetate in hexane gave the pure phenyl itaconate.This compound (23.8 g) was mixed with toluene (200 mL) and the resultingsolution treated with trifluoroacetic acid (30 mL). The solution wasstirred at room temperature for 1.5 hour and then evaporated. Theresidue was taken up in ether (150 mL) and treated withdicyclohexylamine (10.4 g) and stirred at 0° whereupon the saltprecipitated. This was isolated by filtration and washed with hexane anddried to give pure 1-benzyl 2-benzylidene succinoatedicyclohexylammonium salt (21.24 g, 73% yield). This benzylidenecompound (20 g) was place in a Fisher-Porter bottle and also added weredegassed methanol (200 mL) and rhodium (R,R) DiPAMP (600 mg) catalyst.The bottle was sealed and flushed with nitrogen then hydrogen. Thereaction was hydrogenated at 40 psig for 15 hours at room temperature.The contents were then poured into a round bottom flask (500 mL) and thesolvent evaporated to give a dark solid. The residue was taken up inboiling isooctane and allowed to stand, with some title compoundcrystallizing (7.34 g). The non-dissolved residue was taken up inboiling dimethoxyethane. This solution was allowed to cool for 12 hours,whereupon crystals of the title compound formed (6.05 g). Combining thetwo crops gave 13.39 g, 66% yield, mp 122°-125°. 300 MHz ¹ H NMR:consistent with proposed structure.

Step 9

2R-(Phenylmethyl)butanedioic acid, 1-(phenylmethyl) ester

The title compound of Step 8 (9.3 g) was suspended in a mixture of water(84 mL) and methanol (8.5 mL). Solid sodium bisulfate (6.12) was addedand the mixture stirred for 5 minutes. The mixture was extracted withmethylene chloride and the combined extracts were dried over magnesiumsulfate and evaporated to dryness. The residue was chromatographed onsilica gel, eluting with methanol-chloroform-acetic acid (5:95:0.5), togive the pure title compound (4.3 g, 74% yield).

Step 10

4-[2(N-Formylamino)ethyl]morpholine

The procedure of B. V. Cheney et al. [J. Med. Chem., 28, 1853-1864(1985)) was used. A solution of 4-(2-aminoethyl)morpholine (1.00 g, 76.8mmol) and ethyl formate (213 mL, 2640 mmol) was refluxed overnight underan atmosphere of nitrogen. Vacuum distillation gave 11.46 g (100% yield)of a clear, colorless liquid (bp₀.3 118°-120° C.). The 1H NMR spectraldata were consistent with the structure of the title compound.

Step 11

4-[2-Methylamino)ethyl]morpholine

A solution of the title compound of Step 10 in anhydrous tetrahydrofuran(50 mL) was added dropwise to a solution of lithium aluminum hydride(8.07 g, 213 mmol) in anhydrous tetrahydrofuran (505 mL) at roomtemperature. The mixture was refluxed overnight. To the reactionsolution was added H₂ O (8.0 mL), a 15% NaOH solution (8.0 mL), and H₂ O(24 mL). The filtrate was vacuum distilled to give 4.94 g (72% yield) ofthe title compound as a clear, colorless liquid (bp₁₀ 74°-76° C.). Theproton and carbon NMR spectral data were consistent with the proposedstructure.

Step 12

PhenylmethylαR-[2-[methyl[2-(4-morpholinyl)ethyl]amino]-2-oxoethyl]benzenepropanoate

To a solution of the title compound of Step 9 (0.72 g, 2.43 mmol) andpyridine (0.19 g, 2.43 mmol) in methylene chloride (8 mL) was addedN,N'-disuccinimidyl carbonate (DSC, 0.62 g, 2.4 mmol) anddimethylaminopyridine DMAP, 18 mg). After 3 hours, the title compound ofStep 11 (0.35 g, 2.43 mmol) was added and the solution stirredovernight. The reaction mixture was diluted with CH₂ Cl₂ (12 mL) andthen was washed with 5% aqueous K₂ CO₃ solution (2×5 mL), H₂ O (10 mL),and brine (10 mL). The organic layer was dried over MgSO₄. The filtratewas concentrated and purified by medium pressure column chromatography(silica gel, 3% MeOH in CHCl₃, Rf=0.08) to give 0.925 g (89% yield) ofthe title compound as an oil. The proton NMR spectral data wereconsistent for the proposed structure.

Step 13

αR-[2-[methyl[2-(4-morpholinyl)ethyl]aminol-2-oxoethyl]benzenepropanoicacid

A mixture of the title compound of Step 12 (0.632 g, 1.49 mmol) and 4%Pd/C (0.070 g) in EtOH (10 mL) was placed under a hydrogen atmospherewith a balloon for 18 hours. The mixture was filtered through a celitebed. The filtrate was concentrated to give 0.486 g (98% crude yield) ofthe title compound as a white foam. The proton NMR spectral data wasconsistent with the proposed structure.

The following working Example is provided to illustrate synthesis ofCompounds 1-20 of the present invention and are not intended to limitthe scope thereof. Those skilled in the art will readily understand thatknown variations of the conditions and processes of the followingpreparative procedures can be used to prepare the compounds of theExamples. All temperatures expressed are in degrees Centigrade.

EXAMPLE 1 ##STR7##

The acid of Step 13 (150 mg) was dissolved in methylene chloride (1 mL)at room temperature and pyridine (36 mL) was added, followed by solidN,N'-disuccinimidyl carbonate (114 mg). Dimethylaminopyridine (15 mg)was next added. Gas evolution ensued and ceased after 0.5 hour. Afterstirring at room temperature for 2 hours, the amine of Step 7 (136 mg)was added as a solid. The reaction mixture was then allowed to stir for12 hours, whereupon the solvent was evaporated at reduced pressure andthe residue was taken up in methanol. To this solution was added 5 dropsof 5% aqueous potassium carbonate solution. After the mixture stood for15 minutes, the methanol was evaporated at reduced pressure and theresidue partitioned between ethyl acetate and 5% aqueous potassiumcarbonate. The organic layer was then washed successively with 5%aqueous potassium carbonate, water and brine and evaporated to a yellowfoam (236 mg). This was chromatographed on silica gel, eluting withmethylene chloride-methanol (9:1) to give the pure title compound (120mg, 45% yield) as a white foam. 1H NMR (CDCl₃): consistent with proposedstructure. Anal. calcd. for C₃₇ H₅₈ N₄ O₆ : C, 67.86; H, 8.93; N, 8.56.Found: C, 67.45; H, 9.05; N, 8.36.

Compounds #2-20, as shown in Table I below, may be synthesized byreference to the foregoing specific and general procedures for preparingcompounds of Formula I.

                                      TABLE I                                     __________________________________________________________________________    Example                                                                       Compound No.                                                                          Structure                                                             __________________________________________________________________________     2                                                                                     ##STR8##                                                              3                                                                                     ##STR9##                                                              4                                                                                     ##STR10##                                                             5                                                                                     ##STR11##                                                             6                                                                                     ##STR12##                                                             7                                                                                     ##STR13##                                                             8                                                                                     ##STR14##                                                             9                                                                                     ##STR15##                                                            10                                                                                     ##STR16##                                                            11                                                                                     ##STR17##                                                            12                                                                                     ##STR18##                                                            13                                                                                     ##STR19##                                                            14                                                                                     ##STR20##                                                            15                                                                                     ##STR21##                                                            16                                                                                     ##STR22##                                                            17                                                                                     ##STR23##                                                            18                                                                                     ##STR24##                                                            19                                                                                     ##STR25##                                                            20                                                                                     ##STR26##                                                            21                                                                                     ##STR27##                                                            __________________________________________________________________________

BIOLOGICAL EVALUATION

Human Renin Inhibition in vitro

Compounds of Formula I were evaluated as inhibitors of human renin in anin vitro assay, as follows: This human renin inhibition test has beenpreviously described in detail [Papaicannou et al., Clinical andExperimental Hypertension, A7(9), 1243-1257 (1985)]. Human renin wasobtained from the National Institute for Biological Standards, London.An incubation mixture was prepared containing the following components:in a total volume of 0.25 mL: 100 mM Tris-acetate buffer at ph 7.4,25×10⁻⁶ Goldblatt units of renin, 0.05 mL of plasma from humanvolunteers taking oral contraceptives, 6.0 mM Na-EDTA, 2.4 mMphenylmethyl sulfonyl fluoride, 1.5 mM 8-hydroxyquinoline, 0.4 mg/mLbovine serum albumin (BSA), and 0.024 mg/mL neomycin sulfate. Thismixture was incubated for two hours at 37° C. in the presence or absenceof renin inhibitors. The produced angiotensin I was determined byradioimmunoassay (New England Nuclear kit). Test compounds to be assayedwere dissolved in DMSO and diluted with 100 mM Tris-acetate buffer at pH7.4 containing 0.5% BSA to the appropriate concentration. The finalconcentration of organic solvent in the reaction mixture was less than1%. Control incubations at 37° C. were used to correct for effects oforganic solvent on renin activity. The in vitro enzymatic conversion ofangiotensinogen to angiotensin I was inhibited by test compound of theinvention as indicated in Table II, below:

Table II

Human Renin in vitro Inhibition Data

                  TABLE II                                                        ______________________________________                                        Human Renin in vitro Inhibition Data                                          Compound Example #                                                                            IC.sub.50 Human Renin (nM)                                    ______________________________________                                        Example 1       1                                                             ______________________________________                                    

Also embraced within this invention is a class of pharmaceuticalcompositions comprising one or more compounds of Formula I inassociation with one or more non-toxic, pharmaceutically acceptablecarriers and/or diluents and/or adjuvants (collectively referred toherein as "carrier" materials) and, if desired, other activeingredients. The compounds of the present invention may be administeredby any suitable route, preferably in the form of a pharmaceuticalcomposition adapted to such a route, and in a dose effective for thetreatment intended. Therapeutically effective doses of the compounds ofthe present invention required to prevent or arrest the progress of themedical condition are readily ascertained by one of ordinary skill inthe art. The compounds and composition may, for example, be administeredintravascularly, intraperitoneally, subcutaneously, intramuscularly ortopically.

For oral administration, the pharmaceutical composition may be in theform of, for example, a tablet, capsule, suspension or liquid. Thepharmaceutical composition is preferably made in the form of a dosageunit containing a particular amount of the active ingredient. Examplesof such dosage units are tablets or capsules. These may with advantagecontain an amount of active ingredient from about 1 to 250 mg,preferably from about 25 to 150 mg. A suitable daily dose for a mammalmay vary widely depending on the condition of the patient and otherfactors. However, a dose of from about 0.1 to 3000 mg/kg body weight,particularly from about 1 to 100 mg/kg body weight, may be appropriate.

The active ingredient may also be administered by injection as acomposition wherein, for example, saline, dextrose or water may be usedas a suitable carrier. A suitable daily dose is from about 0.1 to 100mg/kg body weight injected per day in multiple doses depending on thedisease being treated. A preferred daily dose would be from about 1 to30 mg/kg body weight. Compounds indicated for prophylactic therapy willpreferably be administered in a daily dose generally in a range fromabout 0.1 mg to about 100 mg per kilogram of body weight per day. A morepreferred dosage will be a range from about 1 mg to about 100 mg perkilogram of body weight. Most preferred is a dosage in a range fromabout 1 to about 50 mg per kilogram of body weight per day. A suitabledose can be administered, in multiple sub-doses per day. These sub-dosesmay be administered in unit dosage forms. Typically, a dose or sub-dosemay contain from about 1 mg to about 400 mg of active compound per unitdosage form. A more preferred dosage will contain from about 2 mg toabout 200 mg of active compound per unit dosage form. Most preferred isa dosage form containing from about 3 mg to about 100 mg of activecompound per unit dose.

The dosage regimen for treating a disease condition with the compoundsand/or compositions of this invention is selected in accordance with avariety of factors, including the type, age, weight, sex and medicalcondition of the patient, the severity of the disease, the route ofadministration, and the particular compound employed, and thus may varywidely.

For therapeutic purposes, the compounds of this invention are ordinarilycombined with one or more adjuvants appropriate to the indicated routeof administration. If administered per os, the compounds may be admixedwith lactose, sucrose, starch powder, cellulose esters of alkanoicacids, cellulose alkyl esters, talc, stearic acid, magnesium stearate,magnesium oxide, sodium and calcium salts of phosphoric and sulfuricacids, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone,and/or polyvinyl alcohol, and then tableted or encapsulated forconvenient administration. Such capsules or tablets may contain acontrolled-release formulation as may be provided in a dispersion ofactive compound in hydroxypropylmethyl cellulose. Formulations forparenteral administration may be in the form of aqueous or non-aqueousisotonic sterile injection solutions or suspensions. These solutions andsuspensions may be prepared from sterile powders or granules having oneor more of the carriers or diluents mentioned for use in theformulations for oral administration. The compounds may be dissolved inwater, polyethylene glycol, propylene glycol, ethanol, corn oil,cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride,and/or various buffers. Other adjuvants and modes of administration arewell and widely known in the pharmaceutical art.

Although this invention has been described with respect to specificembodiments, the details of these embodiments are not to be construed aslimitations.

What is claimed is:
 1. A compound of Formula I: ##STR28## wherein A isselected from CO and SO₂ ; wherein X is selected from oxygen atom andmethylene; wherein R₁ is selected from hydrido and alkyl; wherein B is athiazetidinyl radical having the structure ##STR29## wherein the bonddisected by the wavy line represents a point of attachment of B inFormula I to any attachable position of B, including the nitrogen atomof B, and wherein the bond bisected by the wavy line also represents anysubstitutable position of B; wherein any substitutable position of B maybe substituted with one or more radicals selected from alkyl, alkoxy,alkenyl, alkynyl, halo, trifluoromethyl, oxo, cyano and phenyl, andwherein the ring nitrogen atom of B may be combined with oxygen to forman N-oxide; wherein R₂ is selected from alkyl, cycloalkylalkyl,alkylcarbonylaminoalkyl, phenylalkyl and naphthylalkyl, and wherein thecyclic portion of any of said phenylalkyl, cycloalkylalkyl andnaphthylalkyl groups may be substituted by one or more radicals selectedfrom halo, hydroxy, alkoxy and alkyl; wherein each of R₃ and R₅ isindependently selected from hydrido and alkyl; wherein R₄ is selectedfrom ##STR30## wherein V is selected from hydrido, alkyl, benzyl andphenyl; wherein each of R₈ and R₉ is a radical independently selectedfrom hydrido, alkyl, alkenyl and phenyl; wherein R₆ is selected fromalkyl, cycloalkylalkyl and phenylalkyl, any one of which may besubstituted with one or more groups selected from alkyl, hydroxy andalkoxy; wherein R₇ is selected from alkyl; cycloalkyl, cycloalkylalkyl,hydroxyalkyl and alkenyl; wherein p is a number selected from zerothrough five, inclusive; wherein q is a number selected from zerothrough five, inclusive; and wherein n is a number selected from zerothrough five, inclusive; or a pharmaceutically-acceptable salt thereof.2. Compound of claim 1 wherein A is selected from CO and SO₂ ; wherein Xis selected from oxygen atom and methylene; wherein R₁ is selected fromhydrido and alkyl; wherein B is a thiazetidinyl radical having thestructure ##STR31## wherein the bond bisected by the wavy linerepresents a point of attachment of B in Formula I to any attachableposition of B, including the nitrogen atom of B, and wherein the bondbisected by the wavy line also represents any substitutable position ofB; wherein any substitutable position of B may be substituted with oneor more radicals selected from alkyl, alkoxy, alkenyl, alkynyl, halo,trifluoromethyl, oxo, cyano and phenyl, and wherein the ring nitrogenatom of B may be combined with oxygen to form an N-oxide; wherein R₂ isselected from cyclohexylmethyl, phenylmethyl and naphthylmethyl, andwherein the cyclic portion of any of said phenylmethyl, cyclohexylmethyland naphthylmethyl groups may be substituted by one or more radicalsselected from halo, hydroxy, alkoxy and alkyl; wherein each of R₃ and R₅is independently selected from hydrido and methyl; wherein R₄ isselected from

    --(CH.sub.2).sub.q --C.tbd.C--V

wherein V is selected from hydrido and alkyl; wherein R₆ is selectedfrom cyclohexylmethyl and phenylmethyl, either one of which may besubstituted with one or more groups selected from alkyl, hydroxy andalkoxy; wherein R₇ is selected from alkyl, cycloalkyl andcycloalkylalkyl; wherein q is a number selected from zero through three,inclusive; and wherein n is a number selected from zero through five,inclusive; or a pharmaceutically-acceptable salt thereof.
 3. Compound ofclaim 2 wherein A is selected from CO and SO₂ ; wherein X is selectedfrom oxygen atom and methylene; wherein R₁ is selected from hydrido,methyl, ethyl, isopropyl and n-propyl; wherein B is a thiazetidinylradical having the structure ##STR32## wherein the bond bisected by thewavy line represents a point of attachment of B in Formula I to anyattachable position of B, including the nitrogen atom of B, and whereinthe bond bisected by the wavy line also represents any substitutableposition of B; wherein any substitutable position of B may besubstituted with one or more radicals selected from alkyl, alkoxy,alkenyl, alkynyl, halo, trifluoromethyl, oxo, cyano and phenyl, andwherein the ring nitrogen atom of B may be combined with oxygen to forman N-oxide; wherein R₂ is selected from cyclohexylmethyl, phenylmethyland naphthylmethyl, and wherein the cyclic portion of any of saidphenylmethyl, cyclohexylmethyl and naphthylmethyl groups may besubstituted by one or more radicals selected from halo, hydroxy, alkoxyand alkyl; wherein each of R₃ and R₅ is independently selected fromhydrido and methyl; wherein R₄ is selected from

    --(CH.sub.2).sub.q --C.tbd.C--V

wherein V is selected from hydrido and alkyl; wherein R₆ is selectedfrom cyclohexylmethyl and phenylmethyl, either one of which may besubstituted with one or more groups selected from alkyl, hydroxy andalkoxy; wherein R₇ is selected from alkyl, cycloalkyl andcycloalkylalkyl; wherein q is a number selected from zero through three,inclusive; and wherein n is a number selected from zero through five,inclusive; or a pharmaceutically-acceptable salt thereof.
 4. Apharmaceutical composition comprising a therapeutically-effective amountof a renin-inhibiting compound and a pharmaceutically-acceptable carrieror diluent, said renin-inhibiting compound selected from a family ofcompounds of Formula I: ##STR33## wherein A is selected from CO and SO₂; wherein X is selected from oxygen atom and methylene; wherein R₁ isselected from hydrido and alkyl; wherein B is a thiazetidinyl radicalhaving the structure ##STR34## wherein the bond bisected by the wavyline represents a point of attachment of B in Formula I to anyattachable position of B, including the nitrogen atom of B, and whereinthe bond bisected by the wavy line also represents any substitutableposition B; wherein any substitutable position of B may be substitutedwith one or more radicals selected from alkyl, alkoxy, alkenyl, alkynyl,halo, trifluoromethyl, oxo, cyano and phenyl, and wherein the ringnitrogen atom of B may be combined with oxygen to form an N-oxide;wherein R₂ is selected from alkyl, cycloalkylalkyl,alkylcarbonylaminoalkyl, phenylalkyl and naphthylalkyl, and wherein thecyclic portion of any of said phenylalkyl, cycloalkylalkyl andnaphthylalkyl groups may be substituted by one or more radicals selectedfrom halo, hydroxy, alkoxy and alkyl; wherein each of R₃ and R₅ isindependently selected from hydrido and alkyl; wherein R₄ is selectedfrom ##STR35## wherein V is selected from hydrido, alkyl, benzyl andphenyl; wherein each of R₈ and R₉ is a radical independently selectedfrom alkyl, alkenyl and phenyl; wherein R₆ is selected from alkyl,cycloalkylalkyl and phenylalkyl, any one of which may be substitutedwith one or more groups selected from alkyl, hydroxy and alkoxy; whereinR₇ is selected from alkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl andalkenyl; wherein p is a number selected from zero through five,inclusive; wherein q is a number selected from zero through five,inclusive; and wherein n is a number selected from zero through five,inclusive; or a pharmaceutically-acceptable salt thereof.
 5. Thecomposition of claim 4 wherein A is selected from CO and SO₂ ; wherein Xis selected from oxygen atom and methylene; wherein R₁ is selected fromhydrido and alkyl; wherein B is a thiazetidinyl radical having thestructure ##STR36## wherein the bond bisected by the wavy linerepresents a point of attachment of B in Formula I to any attachableposition of B, including the nitrogen atom of B, and wherein the bondbisected by the wavy line also represents any substitutable position ofB; wherein any substitutable position of B may be substituted with oneor more radicals selected from alkyl, alkoxy, alkenyl, alkynyl, halo,trifluoromethyl, oxo, cyano and phenyl, and wherein the ring nitrogenatom of B may be combined with oxygen to form an N-oxide; wherein R₂ isselected from cyclohexylmethyl, phenylmethyl and naphthylmethyl, andwherein the cyclic portion of any of said phenylmethyl, cyclohexylmethyland naphthylmethyl groups may be substituted by one or more radicalsselected from halo, hydroxy, alkoxy and alkyl; wherein each of R₃ and R₅is independently selected from hydrido and methyl; wherein R₄ isselected from

    --(CH.sub.2).sub.q --C.tbd.C--V

wherein V is selected from hydrido and alkyl; wherein R₆ is selectedfrom cyclohexylmethyl and phenylmethyl, either one of which may besubstituted with one or more groups selected from alkyl, hydroxy andalkoxy; wherein R₇ is selected from alkyl, cycloalkyl andcycloalkylalkyl; wherein q is a number selected from zero through three,inclusive; and wherein n is a number selected from zero through five,inclusive; or a pharmaceutically-acceptable salt thereof.
 6. Thecomposition of claim 5 wherein A is selected from CO and SO₂ ; wherein Xis selected from oxygen atom and methylene; wherein R₁ is selected fromhydrido, methyl, ethyl, isopropyl and n-propyl; wherein B is athiazetidinyl radical having the structure ##STR37## wherein the bondbisected by the wavy line represents a point of attachment of B inFormula I to any attachable position of B, including the nitrogen atomof B, and wherein the bond bisected by the wavy line also represents anysubstitutable position of B; wherein any substitutable position of B maybe substituted with one or more radicals selected from alkyl, alkoxy,alkenyl, alkynyl, halo, trifluoromethyl, oxo, cyano and phenyl, andwherein the ring nitrogen atom of B may be combined with oxygen to forman N-oxide; wherein R₂ is selected from cyclohexylmethyl, phenylmethyland naphthylmethyl, and wherein the cyclic portion of any of saidphenylmethyl, cyclohexylmethyl and naphthylmethyl groups may besubstituted by one or more radicals selected from halo, hydroxy, alkoxyand alkyl; wherein each of R₃ and R₅ is independently selected fromhydrido and methyl; wherein R₄ is selected from

    --(CH.sub.2).sub.q --C.tbd.C--V

wherein V is selected from hydrido and alkyl; wherein R₆ is selectedfrom cyclohexylmethyl and phenylmethyl, either one of which may besubstituted with one or more groups selected from alkyl, hydroxy andalkoxy; wherein R₇ is selected from alkyl, cycloalkyl andcycloalkylalkyl; wherein q is a number selected from zero through three,inclusive; and wherein n is a number selected from zero through five,inclusive; or a pharmaceutically-acceptable salt thereof.
 7. Atherapeutic method for treating a circulatory-related disorder, saidmethod comprising administering to a subject susceptible to or afflictedwith such disorder a therapeutically-effective amount of a compound ofFormula I: ##STR38## wherein A is selected from CO and SO₂ ; wherein Xis selected from oxygen atom and methylene; wherein R₁ is selected fromhydrido and alkyl; wherein B is a thiazetidinyl radical having thestructure ##STR39## wherein the bond bisected by the wavy linerepresents a point of attachment of B in Formula I to any attachableposition of B, including the nitrogen atom of B, and wherein the bondbisected by the wavy line also represents any substitutable position ofB; wherein any substitutable position of B may be substituted with oneor more radicals selected from alkyl, alkoxy, alkenyl, alkynyl, halo,trifluoromethyl, oxo, cyano and phenyl, and wherein the ring nitrogenatom of B may be combined with oxygen to form an N-oxide; wherein R₂ isselected from alkyl, cycloalkylalkyl, alkylcarbonylaminoalkyl,phenylalkyl and naphthylalkyl, and wherein the cyclic portion of any ofsaid phenylalkyl, cycloalkylalkyl and naphthylalkyl groups may besubstituted by one or more radicals selected from halo, hydroxy, alkoxyand alkyl; wherein each of R₃ and R₅ is independently selected fromhydrido and alkyl; wherein R₄ is selected from ##STR40## wherein V isselected from hydrido, alkyl, benzyl and phenyl; wherein each of R₈ andR₉ is a radical independently selected from hydrido, alkyl, alkenyl andphenyl; wherein R₆ is selected from alkyl, cycloalkylalkyl andphenylalkyl, any one of which may be substituted with one or more groupsselected from alkyl, hydroxy and alkoxy; wherein R₇ is selected fromalkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl and alkenyl; wherein pis a number selected from zero through five, inclusive; wherein q is anumber selected from zero through five, inclusive; and wherein n is anumber selected from zero through five, inclusive; or apharmaceutically-acceptable salt thereof.
 8. The method of claim 7wherein A is selected from CO and SO₂ ; wherein X is selected fromoxygen atom and methylene; wherein R₁ is selected from hydrido andalkyl; wherein B is a thiazetidinyl radical having the structure##STR41## wherein the bond bisected by the wavy line represents a pointof attachment of B in Formula I to any attachable position of B,including the nitrogen atom of B, and wherein the bond bisected by thewavy line also represents any substitutable position of B; wherein anysubstitutable position of B may be substituted with one or more radicalsselected from alkyl, alkoxy, alkenyl, alkynyl, halo, trifluoromethyl,oxo, cyano and phenyl, and wherein the ring nitrogen atom of B may becombined with oxygen to form an N-oxide; wherein R₂ is selected fromcyclohexylmethyl, phenylmethyl and naphthylmethyl, and wherein thecyclic portion of any of said phenylmethyl, cyclohexylmethyl andnaphthylmethyl groups may be substituted by one or more radicalsselected from halo, hydroxy, alkoxy and alkyl; wherein each of R₃ and R₅is independently selected from hydrido and methyl; wherein R₄ isselected from

    --(CH.sub.2).sub.q --C.tbd.C--V

wherein V is selected from hydrido and alkyl; wherein R₆ is selectedfrom cyclohexylmethyl and phenylmethyl, either one of which may besubstituted with one or more groups selected from alkyl, hydroxy andalkoxy; wherein R₇ is selected from alkyl, cycloalkyl andcycloalkylalkyl; wherein q is a number selected from zero through three,inclusive; and wherein n is a number selected from zero through five,inclusive; or a pharmaceutically-acceptable salt thereof.
 9. The methodof claim 8 wherein A is selected from CO and SO₂ ; wherein X is selectedfrom oxygen atom and methylene; wherein R₁ is selected from hydrido,methyl, ethyl, isopropyl and n-propyl; wherein B is a thiazetidinylradical having the structure ##STR42## wherein the bond bisected by thewavy line represents a point of attachment of B in Formula I to anyattachable position of B, including the nitrogen atom of B, and whereinthe bond bisected by the wavy line also represents any substitutableposition of B; wherein any substitutable position of B may besubstituted with one or more radicals selected from alkyl, alkoxy,alkenyl, alkynyl, halo, trifluoromethyl, oxo, cyano and phenyl, andwherein the ring nitrogen atom of B may be combined with oxygen to forman N-oxide; wherein R₂ is selected from cyclohexylmethyl, phenylmethyland naphthylmethyl, and wherein the cyclic portion of any of saidphenylmethyl, cyclohexylmethyl and naphthylmethyl groups may besubstituted by one or more radicals selected from halo, hydroxy, alkoxyand alkyl; wherein each of R₃ and R₅ is independently selected fromhydrido and methyl; wherein R₄ is selected from

    --(CH.sub.2).sub.q --C.tbd.C--V

wherein V is selected from hydrido and alkyl; wherein R₆ is selectedfrom cyclohexylmethyl and phenylmethyl, either one of which may besubstituted with one or more groups selected from alkyl, hydroxy andalkoxy; wherein R₇ is selected from alkyl, cycloalkyl andcycloalkylalkyl; wherein q is a number selected from zero through three,inclusive; and wherein n is a number selected from zero through five,inclusive; or a pharmaceutically-acceptable salt thereof.
 10. The methodof claim 7 wherein said circulatory-related disorder is a cardiovasculardisorder.
 11. The method of claim 10 wherein said cardiovasculardisorder is hypertension.
 12. The method of claim 10 wherein saidcardiovascular disorder is congestive heart failure.
 13. The method ofclaim 7 wherein said circulatory-related disorder is glaucoma.
 14. Themethod of claim 7 wherein said circulatory-related disorder is renalfailure.